Dipeptidyl Peptidase 4 Inhibitors Reduce Hepatocellular Carcinoma by Activating Lymphocyte Chemotaxis in Mice
Dipeptidyl Peptidase 4 Inhibitors Reduce Hepatocellular Carcinoma by Activating Lymphocyte Chemotaxis in Mice
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DOI：
10.1016/j.jcmgh.2018.08.008
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发表时间：
2019-01-01
影响因子：
7.2
通讯作者：
Hino, Keisuke
中科院分区：
文献类型：
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作者：
Nishina, Sohji;Yamauchi, Akira;Hino, Keisuke
DPP 4抑制剂通过激活淋巴细胞浸润到小鼠异种移植肿瘤或肝肿瘤中来抑制HCC的发展。背景与目的：CD 26是一种多功能跨膜糖蛋白，在多种癌症中表达，其功能类似于二肽基肽酶4（DPP 4）。我们研究了CD 26的表达是否与肝细胞癌（HCC）的进展，以及是否DPP 4抑制剂发挥抗肿瘤作用对HCC.METHODS：CD 26的表达进行了检查，在41例手术切除的HCC标本。DPP 4抑制剂对肝癌的影响进行了研究，使用肝癌细胞系（Huh-7和Li-7），裸鼠移植瘤，和非酒精性脂肪性肝炎相关的HCC小鼠模型。结果：CD 26在HCC标本中的表达与血清DPP 4活性增加，以及更先进的阶段，肿瘤免疫力下降，肝癌患者预后较差。HCC细胞系和异种移植肿瘤表现出CD 26表达和DPP 4活性。DPP 4抑制剂在体外没有表现出抗肿瘤作用，但在体内自然杀伤细胞（NK）和/或T细胞肿瘤蓄积抑制异种移植肿瘤和HCC的生长。DPP 4抑制剂的抗肿瘤作用通过NK细胞的耗竭或NK细胞上的趋化因子受体CXCR 3的中和而消除。EZ-TAXIScan是一种光学水平趋化装置，在Huh-7细胞和与CXCR 3结合的趋化因子CXCL 10存在的情况下，通过DPP 4抑制剂离体鉴定出增强的NK和T细胞趋化性。DPP 4抑制剂防止CXCL 10的生物活性形式被Huh-7细胞DPP 4活性截短。DPP 4抑制剂也抑制肿瘤血管生成.CONCLUSIONS：这些结果提供了一个合理的验证是否DPP 4抑制剂临床抑制HCC的进展或增强抗肿瘤作用的分子靶向药物或免疫疗法对HCC。
DPP4 inhibitors suppressed HCC development through the activated infiltration of lymphocytes into the xenograft tumors or liver tumors in mice. This effect was exerted by preventing the biologically active form of CXCL10 from being truncated by DPP4 activity.BACKGROUND & AIMS: CD26, a multifunctional transmembrane glycoprotein, is expressed in various cancers and functions as dipeptidyl peptidase 4 (DPP4). We investigated whether CD26 expression is associated with hepatocellular carcinoma (HCC) progression and whether DPP4 inhibitors exert antitumor effects against HCC.METHODS: CD26 expression was examined in 41 surgically resected HCC specimens. The effects of DPP4 inhibitors on HCC were examined by using HCC cell lines (Huh-7 and Li-7), xenograft tumors in nude mice, and a nonalcoholic steatohepatitis-related HCC mouse model.RESULTS: CD26 expression in HCC specimens was associated with increased serum DPP4 activity, as well as a more advanced stage, less tumor immunity, and poorer prognosis in HCC patients. The HCC cell lines and xenograft tumors exhibited CD26 expression and DPP4 activity. The DPP4 inhibitors did not exhibit antitumor effects in vitro, but natural killer (NK) and/or T-cell tumor accumulation suppressed growth of xenograft tumor and HCC in vivo. The antitumor effects of DPP4 inhibitors were abolished by the depletion of NK cells or the neutralization of CXCR3, a chemokine receptor on NK cells. EZ-TAXIScan, an optical horizontal chemotaxis apparatus, identified enhanced NK and T-cell chemotaxis by DPP4 inhibitors ex vivo in the presence of Huh-7 cells and the chemokine CXCL10, which binds to CXCR3. The DPP4 inhibitors prevented the biologically active form of CXCL10 from being truncated by Huh-7 cell DPP4 activity. DPP4 inhibitors also suppressed tumor angiogenesis.CONCLUSIONS: These results provide a rationale for verifying whether DPP4 inhibitors clinically inhibit the progression of HCC or augment the antitumor effects of molecular-targeting drugs or immunotherapies against HCC.